Yunjie Xu^a,b,1, Yingwei Wang^e,1, Jusung An^b,1, Adam C. Sedgwick^d,1, Mingle Li^b, Jianlei Xie^a, Weibin Hu^c, Jianlong Kang^a, Sajal Sen^d, Axel Steinbrueck^d, Bin Zhang^f, Lijun Qiao^c, Swelm Wageh^g, Jonathan F. Arambula^d,*, Liping Liu^c,*, Han Zhang^a,*, Jonathan L. Sessler^d,*, Jong Seung Kim^b,*

^aShenzhen Engineering Laboratory of Phosphorene and Optoelectronics; International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education, Shenzhen Institute of Translational Medicine, Department of Otolaryngology, Shenzhen Second People's Hospital, The First Affiliated Hospital, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China ^bDepartment of Chemistry, Korea University, Seoul, 02841, South Korea ^cDepartment of Hepatobiliary and Pancreatic Surgery, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China ^dDepartment of Chemistry, The University of Texas at Austin, Austin, TX, 78712-1224, USA ^eHunan Key Laboratory of Nanophotonics and Devices, School of Physics and Electronics, Central South University, 932 South Lushan Road, Changsha, 410083, China ^fInstitute of Translation Medicine Shenzhen Second People's Hospital First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China ^gDepartment of Physics, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

¹Those authors contributed equally to this work.

^*Corresponding author.

An increased demand for iron is a hallmark of cancer cells and is thought necessary to promote high cell proliferation, tumor progression and metastasis. This makes iron metabolism an attractive therapeutic target. Unfortunately, current iron-based therapeutic strategies often lack effectiveness and can elicit off-target toxicities. We report here a dual-therapeutic prodrug, DOXjade, that allows for iron chelation chemo-photothermal cancer therapy. This prodrug takes advantage of the clinically approved iron chelator deferasirox (ExJade®) and the topoisomerase 2 inhibitor, doxorubicin (DOX). Loading DOXjade onto ultrathin 2D Ti3C2 MXene nanosheets produces a construct, Ti3C2-PVP@DOXjade, that allows the iron chelation and chemotherapeutic functions of DOXjade to be photo-activated at the tumor sites, while potentiating a robust photothermal effect with photothermal conversion efficiencies of up to 40%. Antitumor mechanistic investigations reveal that upon activation, Ti3C2-PVP@DOXjade serves to promote apoptotic cell death and downregulate the iron depletion-induced iron transferrin receptor (TfR). A tumor pH-responsive iron chelation/photothermal/chemotherapy antitumor effect was achieved both in vitro and in vivo. The results of this study highlight what may constitute a promising iron chelation-based phototherapeutic approach to cancer therapy.

Keywords : 2D MXene, Nanomedicine, Prodrug, Iron chelation, Photothermal therapy